The theme of this Program Project is to elucidate receptor mediated mechanisms involved in the development, normal functioning and modulation of nociceptive transmission relevant to orofacial (trigeminal) pain syndromes. A highly interactive and cohesive group effort will be promoted through active collaboration between investigators with complementary skills, formal research conferences, as well as shared equipment and techniques in a histology core laboratory. Dr. Allan Basbaum will use anatomical and molecular biological techniques to follow the internalization of the substance P receptor and dendritic restructuring occurring after natural sensory stimulation and after intrathecal administration of substance P. He will also evaluate the effects of different opioid analgesics on this internalization. These studies will provide important new information relevant to the pathophysiology and clinical consequences of injury-evoked changes in the spinal cord dorsal horn. Dr. Julius will use in situ hybridization and gene-targeted mutation to study the neuroanatomical distribution and functional role of P/2X ATP receptors in spinal and trigeminal sensory pathways. In addition, he will attempt to isolate a functional cDNA clone encoding the capsaicin receptor. These studies will elucidate receptor mechanisms underlying sensory transduction and synaptic transmission in pain pathways. Dr. Jon Levine will use behavioral, electrophysiological, anatomical and molecular biological techniques to investigate the mechanisms underlying tolerance and physical dependence for the ability of mu-opioids to produce local peripheral antinociception and to inhibit sensitization of peripheral terminals of primary afferent nociceptors. Cross-tolerance studies will be performed to determine at what level tolerance develops and on what cell type the responsible mu-opioid agonist resides. This information may provide a rational basis for the development of strategies to maximize the clinical efficacy of mu-opioid peripherally-acting analgesics when administered locally in the periphery. Dr. Marc Tessier-Lavigne will first characterize and identify a recently discovered attractant factor, "maxillary factor" important in axonal guidance during development in the trigeminal system. Then, employing molecular biological, biochemical and cell biological techniques, he will determine the contribution of maxillary factor in the establishment of developing neuronal connections in the trigeminal system. Understanding the mechanisms involved in the physiological establishment of neuronal connections and the consequences of abnormal functioning of these mechanisms may provide insights into possible etiologies for a variety of neurological disorders as well as shed light on restorative mechanisms promoting axonal regeneration following neural trauma. The multidisciplinary approach employed in this Program Project should significantly increase our understanding of mechanisms relevant to trigeminal pain syndromes and provide insights for the effective management of clinical pain problems of substantial prevalence and morbidity.